N‐methyl‐d‐aspartate receptors: Structure, function, and role in organophosphorus compound poisoning

Abstract

Acute organophosphorus compound (OP) poisoning induces symptoms of the cholinergic crises with the occurrence of severe epileptic seizures. Seizures are induced by hyperstimulation of the cholinergic system, but are enhanced by hyperactivation of the glutamatergic system. Overstimulation of muscarinic cholinergic receptors by the elevated acetylcholine causes glutamatergic hyperexcitation and an increased influx of Ca2+ into neurons through a type of ionotropic glutamate receptors, N‐methyl‐d‐aspartate (NMDA) receptors (NMDAR). These excitotoxic signaling processes generate reactive oxygen species, oxidative stress, and activation of the neuroinflammatory response, which can lead to recurrent epileptic seizures, neuronal cell death, and long‐term neurological damage. In this review, we illustrate the NMDAR structure, complexity of subunit composition, and the various receptor properties that change accordingly. Although NMDARs are in normal physiological conditions important for controlling synaptic plasticity and mediating learning and memory functions, we elaborate the detrimental role NMDARs play in neurotoxicity of OPs and focus on the central role NMDAR inhibition plays in suppressing neurotoxicity and modulating the inflammatory response. The limited efficacy of current medical therapies for OP poisoning concerning the development of pharmacoresistance and mitigating proinflammatory response highlights the importance of NMDAR inhibitors in preventing neurotoxic processes and points to new avenues for exploring therapeutics for OP poisoning.

Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases

“…Due to these properties, its cholesterol scaffold could serve as a model for the further development of novel oxime antidotes. Moreover, as olesoxime provides mitochondria-stabilizing, calcium-modulating, and anti-apoptotic effects [3], it may improve oxidative status and attenuate signs of inflammation, which are characteristic consequences of OP poisoning in survivors [16]. In addition, olesoxime is a ligand of a presumptive mMPT pore regulator, the 18 kD a mitochondrial permeability transition-translocator protein (TSPO), and as such can play an important role in neuroprotection both by modulating the endogenous production of neurosteroids in the nervous system, and by regulating the MPT process [52,53].…”

“…Both enzymes can be found in the synapses of the central nervous system, neuromuscular junctions of the peripheral nervous system, and in blood where AChE is bound to the erythrocyte membrane and BChE is dissolved in plasma [15]. Poisoning induces a plethora of symptoms like miosis, bronchorrhea, bradycardia, convulsions, and in severe poisoning cases loss of consciousness and respiratory failure, as well as long-term neurological damage in survivors [14,16]. Prevention of seizures and recovery of enzyme activity is the primary goal of therapy, which generally involves the administration of anticholinergic atropine and an oxime reactivator of phosphylated AChE [14].…”